Indene-Based Scaffolds. 2. An Indole−Indene Switch: Discovery of Novel Indenylsulfonamides as 5-HT₆ Serotonin Receptor Agonists

Abstract

Scaffold selection involving an indole-to-indene core change led to the discovery of a series of indenylsulfonamides that act as 5-HT6 serotonin receptor agonists. The variety of the targeted ligands and their synthetic complexity required multistep synthetic approaches. The novel indenylsulfonamides exhibited variable binding affinities for the 5-HT6 receptor, and the in vitro primary binding profiles of the preferred compounds revealed them to be 5-HT6 receptor agonists with Ki values > or =4.5 nM. The structural changes responsible for enhancing the affinities indicated a directing effect modulated by the nature of the indene core, the substitution at the aminoethyl side chain, and especially by the aryl(heteroaryl)sulfonyl group on the indene 5-position. A representative of the family, the N-(inden-5-yl)imidazothiazole-5-sulfonamide (43), exhibited a high affinity and functioned as a potent full agonist for the 5-HT6 receptor (Ki = 4.5 nM, EC50 = 0.9 nM, Emax = 98%).

Therapeutic Potential of 5-HT6 Receptor Agonists

“…61,62 The hit compound 21 behaved as a full agonist of 5-HT 6 R, featuring strong binding affinity (K i = 4.5 nM; EC 50 = 0.9 nM). Moreover, this compound was highly selective over the adrenergic α receptors (IC 50 > 1000 nM) and the serotonergic 5-HT 1A and 5-HT 2C R (IC 50 > 1000 nM).…”

Synthetic approaches to multifunctional indenes

“…In addition, indene-based structures are a source of bioactive compounds in drug discovery and development [10–18]. The routes to access multiply substituted indenes with at least two different functional groups (FGs) are generally complex, and the synthetic approaches leading to these compounds lag behind those for heteroaromatic systems, e.g., indoles, being limited as it is by the scarce knowledge of indene chemistry in comparison with heterocyclic chemistry [3,17–22].…”

“…During the course of our studies on indene-based ligands of general type 1 with biological effects on the central nervous system, we found that different stepwise synthetic routes could be applied to inden-5-amines 2 bearing a disubstituted N , N -aminoethyl side arm at the indene 3-position [17–18]. After analyzing reasonable synthetic routes to the [3-(aminoethyl)inden-5-yl)]amine intermediates 2 starting from substituted indan-1-one 5 , route A was chosen as the most suitable way of functionalizing the 5-position of the indene, e.g., by changing the aryl(heteroaryl) structural motif of a sulfonamide moiety (Scheme 1).…”

“…After analyzing reasonable synthetic routes to the [3-(aminoethyl)inden-5-yl)]amine intermediates 2 starting from substituted indan-1-one 5 , route A was chosen as the most suitable way of functionalizing the 5-position of the indene, e.g., by changing the aryl(heteroaryl) structural motif of a sulfonamide moiety (Scheme 1). This route proceeded in three steps, and allowed the representative (3-indenyl)acetic acids 4 to be conveniently prepared from nitroindanones 5 and the lithium salt of ethyl acetate [18]. …”

“…The aldol-type reaction of indanone 5 with the lithium salts of different N , N -disubstituted acetamides, followed immediately by dehydration afforded the (3-indenyl)acetamides 3 . The success of this route, however, depends on two main factors: (i) The nature of the lithiated base used to deprotonate acetamides in order to form lithium enolates, which needs to be considered when adjusting the reaction conditions [25]; and (ii) the chemical response of indanoles towards dehydration [6,18] to give the desired endo -olefin 3 , which should be favored with the presence of a methyl group at the indene 2-position.…”